ABSTRACT Endometriosis is a chronic inflammatory and painful condition that affects 176 million women in their reproductive years worldwide, and has substantial costs related to health care and loss in work productivity. The symptoms of endometriosis?chronic, incapacitating pain and infertility?cause high levels of stress, leading to poor quality of life (QoL) in affected women. Stress is known to affect the physiology of pelvic organs and to disturb the HPA axis leading to chronic, painful, inflammatory disorders. We have documented a relationship between stress, HPA dysregulation and endometriosis. In an animal model we demonstrated that stress exacerbates disease manifestations whereas the ability to control the level of stress results in smaller lesions and less inflammation. Further, we have identified social support as one of the parameters that most significantly impacts QoL in women with endometriosis. Environmental enrichment (EE) can produce beneficial effects in models of chronic diseases improving anxiety and immune-related disturbances, and can block the effects of chronic stress on brain hippocampal integrity. We recently found that EE can effectively minimize lesion size and numbers, and also decreased anxiety in this animal model. Together, these data support the basic premise of this proposal: EE interventions can overcome chronic stress thus reversing the negative influences on mental health status (depression/anxiety levels), inflammation/HPA axis (inflammatory cytokines, cortisol), and clinical course (pain levels) of endometriosis, leading to improved QoL. The central objective of this study is to refine and test a multi-modal intervention based on the EE paradigm tested in our animal model and translated it to the human scenario, to produce data on its effectiveness. We hypothesize that the EE interventions can be effectively adapted for women with endometriosis resulting in pain reduction and improved QoL. To test our hypothesis, our multidisciplinary team with combined expertise in endometriosis, psychology, physiology, neuroscience, gynecology, and stress management has adapted the experimental EE model to the human scenario. By applying a combined approach (systematic review of the literature, and input from a patient advisory committee) the team has jointly developed six EE modules to be tested in human subjects. This study consists of two specific aims. In Aim 1, we will assess feasibility and acceptability of the EE intervention as adjuvant to standard of care through a collaborative approach involving a patient population, while also assessing effectiveness of the recruitment strategies used (e.g., physician?s office vs. print and social media). Under Aim 2, we will conduct a randomized clinical trial (RCT) of the EE intervention to determine its efficacy in improvement of pelvic pain and QoL (primary outcomes), and inflammation, HPA axis disturbances, and mental health (depression, anxiety) (secondary outcomes), measured before, during and after completion of the intervention. With this purpose, we will use a case-control study design for the RCT where cases will receive the adapted EE intervention as an adjuvant to standard gynecologic care for endometriosis, while controls will receive standard of care only. The proposed work will produce a clinically useful multi-level integrative medicine model to be used in stress- and inflammation-related disorders that can easily be implemented with current pharmacological interventions to alleviate pain and improve QoL. Importantly, our proposal addresses high priority areas of the NICHD, namely i) studies on ?environmental and psychosocial factors underlying the etiology of chronic gynecologic pain syndromes?; ii) development of ?novel, non-hormonal pharmacologic treatments for gynecologic disorders?, and iii) ?transdisciplinary research based on findings from diverse fields to advance basic and mechanistic understanding of gynecologic health and disease?.